PROJECT SUMMARY/ABSTRACT The long-term goal of this project is to identify the mechanisms of germ cell sensitivity to environmental exposures and their long-lasting, transgenerational effects. Germ cells are the bridge between generations and their integrity is paramount to the health and viability of all organisms. As such, the dysregulation of germ cells development and function significantly contributes to infertility and is also the leading cause of birth defects and infant deaths in the United States. While the intricate steps of germ cell development have long been hypothesized to provide unique windows of sensitivity to environmental insults, little is known of the effect of chemical exposure on the epigenome of germ cells and of the mechanisms of inheritance of these effects. This gap is particularly significant as embryonic germ cells undergo an extensive remodeling of their chromatin which includes genome-wide demethylation and the establishment of a complex pattern of histone modifications. The failure to properly regulate these histone marks leads to spurious repetitive element expression, germ cell death and infertility. Furthermore, preliminary evidence gathered in the powerful genetic model system C. elegans indicates that exposure to chemicals such as Bisphenol A leads to a heritable, transgenerational defect in chromatin silencing of repetitive DNA. Here, we propose to leverage two complementary germ cell models, the nematode C. elegans and in vitro generated mouse germ cells, to elucidate the molecular mechanisms underlying the epigenetic effects of Bisphenol A. We will achieve this goal by (1) Characterizing the sensitivity of early mammalian germ cells to BPA exposure and establish the long term, transgenerational outcome on reproduction in C. elegans; (2) Providing a comprehensive and detailed examination of epimutations caused by BPA and of their transcriptional consequence; and finally by (3) Identifying the genetic requirements for both germ cell sensitivity to direct exposure as well as for the transmission of epigenetic effects across generations. We expect this research to provide a much-needed examination of the pathways implicated in the sensitivity of early germ cells to environmental insults and at the root of infertility.